Aug 7, 2019, 14:00 PM by Rhashedah A. Ekeoduru, MD, Rohit Rahangdale, MD

Authors

Rhashedah A. Ekeoduru, MD
Resident Physician

Rohit Y. Rahangdale, MD
Assistant Professor

Department of Anesthesiology 
Northwestern University Feinberg School of Medicine
Chicago, Illinois

Introduction 

Soresi first described the benefits of injecting anesthetics through a needle (not a catheter) both in the subarachoid and epidural spaces in 1937.¹  The first documented combined spinal epidural (CSE) procedure with placement of an epidural catheter was performed in 1979 by Curelaru, using the separate needle technique^.2  Today CSE is commonly used for obstetric, gynecologic, orthopedic, urologic and general surgery anesthesia.

Combined spinal epidural anesthesia plays a valuable role in the armamentarium of anesthesiologists by offering many of the advantages of spinal and epidural anesthesia while minimizing the risks associated with each technique.³  Proper use of this technique requires an intimate understanding of the interrelationship of the epidural space, its contents, and the thecal sac.  Additionally, one must pay attention to the potential complications, technical aspects, and limitations of the procedure.

Advantages of CSE 

CSE versus Epidural 

Epidural anesthesia may be associated with incomplete sensory blockade and poor sacral spread.⁴  It however allows for gradual dosing and thus intermittent assessment of completeness of sensory blockade and change in blood pressure.  A CSE with a low-dose spinal anesthetic can achieve similarly stable hemodynamics, while reliably producing dense, non-patchy sensory blockade with improved sacral spread when compared to epidural anesthesia alone.⁵

One proposed explanation for the improved block following CSE is the phenomenon of local anesthetic flux through the dural puncture site.  Suzuki et al.⁶  demonstrated enhanced caudal spread of local anesthetic when the dura was punctured with a 26-gauge spinal needle prior to an epidural bolus when compared to patients who received an epidural alone. Other studies demonstrated no detectable flux when 27 or 29-gauge spinal needles were used.^4,7  Case reports have described inadvertent dural puncture from the epidural Tuohy needle resulting in a total spinal secondary to local anesthetic flux.  Therefore, the size of the needle used for dural puncture appears to be the primary determinant for the amount, if any, of local anesthetic flux that occurs.  Presumably, multiple dural punctures would also increase the amount of flux that occurs. 

Another proposed explanation for the improved success rate of the CSE technique is that the spinal needle may aid in correct identification of the epidural space.  A spinal needle with adequate CSF return when using a needle-through-needle CSE technique suggests proper placement of the Tuohy needle in the epidural space.  Without this confirmation, a false loss of resistance can result in a catheter being placed in area outside the epidural space.  A 2005 study by Norris et al. showed a 1.3% of epidural catheters placed with an epidural technique produced no sensory or motor changes and were likely never in the epidural space^.8  This same study showed that catheters placed with a CSE technique had a lower incidence of failure than an epidural technique⁸

A 2005 study by Miro et al.⁹  in 6497 parturients found a nearly two-fold increase in the catheter replacement rate in patients receiving epidurals compared to the CSE group.  However, the disadvantages of CSE cited in this study included higher reported incidences of pruritus, paresthesias, and back pain.

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Table 1. Incidences of Pruritus, Paresthesias, Back Pain and Ineffective Analgesia Requiring Catheter Replacement: A Comparison between Epidurals and CSE⁹

	Epidural Group (N=4,533) n (%)	CSE Group (N=1,964) n (%)	P Value
Pruritus	437 (10.5)	384 (20.8)	<0.001
Paresthesias	1,346 (36.9)	634 (40.6)	0.014
Back pain	420 (11.6)	232 (14.3)	0.008
Ineffective analgesia requiring catheter replacement	258 (6.2)	63 (3.4)	<0.001

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From: Miro M., Guasch E., Gilsant F.  Comparison of epidural analgesia with combined spinal epidural analgesia for labor: a retrospective study of 6,497 cases.  Intl J Obstet Anesth 2008;17:15-19

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CSE versus Spinal 

 

Spinal anesthesia can cause an abrupt onset of hypotension due to rapid sympathetic blockade.  This can be undesirable in patients with limited cardiac reserve or depleted intravascular volume.  With a CSE technique, the initial low anesthetic dose administered intrathecally can achieve a rapid onset of block yet the epidural catheter inserted can be used later to ensure an adequate level of sensory blockade, and to prolong the block for surgical anesthesia or post-operative analgesia. 

Epidural Volume Extension (EVE) 

Proper use of the CSE technique requires an understanding of the interrelationship between the thecal sac and the epidural space.  Administration of an epidural fluid bolus may increase pressure in the  epidural compartment resulting in compression of the thecal sac.  An MRI study revealed that the thecal sac is maximally compressed 5 minutes after an epidural fluid bolus, with effects lasting for up to 30 minutes.¹⁰  During CSE, epidural bolus injection and thecal sac compression can lead to enhanced cephalad spread of the spinal anesthetic in the intrathecal space.¹¹  This volume based phenomenon is termed epidural volume extension (EVE), epidural volume expansion, or epidural top-up.  Saline or local anesthetic appear to have similar effects on enhanced spinal anesthetic spread. 

Timing of the epidural bolus, and local anesthetic baricity further determine the extent of EVE.   If the epidural bolus is administered shortly after the spinal dose, intrathecal spread is more pronounced than when it is given more than 20 minutes after the spinal dose.¹²  In a study involving male patients undergoing lower extremity surgery, CSE anesthesia performed in the sitting position using isobaric bupivacaine resulted in enhanced cephalad spread following epidural bolus administration but this was not seen with hyperbaric bupivacaine.¹³  Other studies, however, have shown cephalad EVE with the use of hyperbaric bupivicaine if the epidural bolus was administered within 5 minutes of the spinal dose.¹⁴ 

As mentioned earlier, when using 27 or 29-gauge spinal needles, local anesthetic flux from the epidural to subarachnoid space does not appear to contribute to enhanced spinal blockade.  This is confirmed by the finding that both block quality and the extent of cephalad spread is the same irrespective of epidural local anesthetic (in low concentrations) or saline bolus injection.  Furthermore, 5 mL of saline was noted to be as effective as 10, 15 or 20 mL with regards to enhancing cephalad spread.¹⁵  Block height is typically extended by two to four dermatomes.^14,16  EVE is an important phenomen to consider when using the CSE technique, and explains why an otherwise normal dose of spinal anesthetic can result in a high spinal blockade.  

The study by Irita et al.¹⁷ examined the incidence of cardiac arrest and death due to improper anesthetic management in patients receiving CSE, spinal, and epidural anesthesia. There is essentially no difference in the cardiac arrest rate and mortality between the CSE and spinal anesthetic groups.  Epidural anesthesia, however, was associated with higher cardiac arrest and mortality rates.

 

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Table 2. Incidences of Cardiac Arrest and Mortality Due to Anesthetic Management.¹⁷

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	Cardiac Arrest per  10,000 patients	Death per 10,000 patients
CSE	0.55	0.00
Spinal Anesthesia	0.54	0.02
Epidural Anesthesia	0.72	0.14

 

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Technical Considerations

 

Combined Spinal Epidurals can be placed using two primary techniques, the needle-through-needle technique (NTN) and the separate-needle technique (SN).  The SN technique allows for testing the epidural catheter prior to administering the spinal anesthetic.  The NTN is quicker to perform and better tolerated by patients.

The separate-needle (SN) combined spinal epidural technique involves two separate needle punctures, one to place the epidural catheter and one to deposit the spinal anesthetic dose.  With this technique, the practitioner can test the function of the epidural catheter prior to spinal anesthetic administration.  The epidural catheter can be bolused with a fasting acting local anesthetic to assess for uniform bilateral spread.  Because the spinal needle is inserted after epidural catheter placement, there is a theoretical risk of epidural catheter shearing by the spinal needle but this complication has yet to be reported. 

With the NTN technique, the epidural catheter location is not tested prior to spinal anesthetic administration.  Success with the SN and NTN techniques differs.  Casati et al.¹⁸  found that both SN and NTN had a similar failure rate. However, a large scaled study by Sadashivaiah et al.¹⁹ in 4950 patients showed that the SN technique was associated with a lower block failure rate and fewer general anesthetic supplementation than the NTN technique for caesarean section. 

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Table 3. General Anesthesia Conversion Rates for Different Regional Techniques for Caesarean Section¹⁹

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SSS = single shot spinal; NTN CSE = needle through needle combined spinal epidural; SN CSE = separate needle combined spinal epidural

 

From: Sadashivaiah S, Wilson R, McLure H, et al. Double-spaced combined spinal-epidural technique for elective caesarean section: a review of 10 years’ experience in a UK teaching maternity unit.  Intl J Obstet Anesth 2010;19:183-187

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Needle-through-needle (NTN) CSE technique involves administration of the spinal anesthetic dose prior to threading of the epidural catheter (Figures 1 and 2).  When compared to the SN technique, this technique involves needle insertion at a single spinal interspace, thus shortening surgery readiness time (22.7 minutes versus 29.8 minutes).¹⁸  Care must be taken to prevent unintentional spinal needle movement during the NTN technique.  Because the spinal needle is passing through the epidural needle and is not embedded in tissue, it is particularly vulnerable to movement resulting in deposition of only a partial dose of the intended intrathecal anesthetic.²⁴  Excessive spinal needle advancement can lead to anterior dural perforation and theoretically increase the risk of post-dural puncture headache.  External fixation devices designed for the CSEcure and the Adjustable Durasafe CSE needle have been created to stabilize the spinal needle and syringe during intrathecal injection.²⁵  These external fixation devices have been complicated by a loss of tactile discrimination during dural perforation, 15.3% with CSEcure and 25% with Adjustable Durasafe.²⁵  Additionally, poor control of the epidural needle might result in a dural puncture with the Tuohy needle.  However, CSEs have not been associated with an increased incidence of post-dural puncture headache in experienced hands.²⁶  One frequently cited advantage of the NTN CSE technique is the ability to advance the spinal needle as confirmation of epidural needle tip location.  Once cerebrospinal fluid (CSF) is obtained through the spinal needle, one may assume that the epidural needle tip is in proper position in the epidural space. 

 

Failure to obtain CSF with the NTN technique can be attributed to a lack of spinal needle protrusion beyond the epidural needle tip.  Joshi found a 15% failure rate of CSF return when the spinal needle protruded 10 mm past the tip of the Tuohy needle and a 0% failure rate with a 13 mm protrusion.²⁷  These findings are substantiated by Riley who reported a 17% failure rate when a 120 mm Sprotte needle protruded 9 mm past the Tuohy tip, compared with a 0% failure when a 127 mm Gertie Marx needle protruded 17 mm past the Tuohy needle tip.²⁸  Thus failure to obtain an adequate spinal blockade can be attributed to a non-midline approach, excessive movement of the spinal needle within the epidural needle, and inadequate spinal needle protrusion the past the epidural needle tip (minimum 12-13 mm).

Longer spinal needles increase the likelihood of anterior dural puncture and CSF leak.  Riley et al.²⁸  reported a higher incidence of post-dural puncture headache and blood patch requirement in the 127 mm Gertie Marx group than the 120 mm Sprotte group but this difference was not statistically significant. Longer spinal needles may also cause transient paresthesias.  Herbstman noted a 29% incidence of paresthesias with Gertie Marx needles compared to a 17% incidence with the shorter Whitacre needle.²⁹ 

Pharmacological Choices for CSE 

Sufentanil and Fentanyl are the most commonly used intrathecal opioids administered for labor anesthesia to supplement low-dose local anesthetic (e.g., isobaric bupivacaine, ropivicaine or levobupivacaine) to provide a dense sensory block while preserving motor function.  Standard intrathecal Sufentanil doses are 2.5-10 mcg with an ED50 of 2.6 mcg (Table 4.⁴  Standard intrathecal Fentanyl doses are 10-25 mcg with an ED50 of 5.5 mcg⁴  These opioids cause rapid (within 5 minutes) and dense pain relief during stage 1 and 2 of labor.³⁴  Intrathecal Morphine and Meperidine have delayed onset time and a higher incidence of delayed respiratory depression, pruritus, nausea, and vomiting^4,34

Needle-through-needle (NTN) CSE technique involves administration of the spinal anesthetic dose prior to threading of the epidural catheter.  When compared to the SN technique, this technique involves needle insertion at a single spinal interspace, thus shortening surgery readiness time (22.7 minutes versus 29.8 minutes).¹⁷  Care must be taken to prevent unintentional spinal needle movement during the NTN technique.  Because the spinal needle is passing through the epidural needle and is not embedded in tissue, it is particularly vulnerable to movement resulting in deposition of only a partial dose of the intended intrathecal anesthetic.²³  Excessive spinal needle advancement can lead to anterior dural perforation and theoretically increase the risk of post-dural puncture headache.  External fixation devices designed for the CSEcure and the Adjustable Durasafe CSE needle have been created to stabilize the spinal needle and syringe during intrathecal injection.²⁴  These external fixation devices have been complicated by a loss of tactile discrimination during dural perforation, 15.3% with CSEcure and 25% with Adjustable Durasafe^.24 Additionally, poor control of the epidural needle might result in a dural puncture with the Tuohy needle.  However, CSEs have not been associated with an increased incidence of post-dural puncture headache in experienced hands.²⁵  One frequently cited advantage of the NTN CSE technique is the ability to advance the spinal needle as confirmation of epidural needle tip location.  Once cerebrospinal fluid (CSF) is obtained through the spinal needle, one may assume that the epidural needle tip is in proper position in the epidural space. 

Failure to obtain CSF with the NTN technique can be attributed to a lack of spinal needle protrusion beyond the epidural needle tip.  Joshi found a 15% failure rate of CSF return when the spinal needle protruded 10 mm past the tip of the Tuohy needle and a 0% failure rate with a 13 mm protrusion.²⁶  These findings are substantiated by Riley who reported a 17% failure rate when a 120 mm Sprotte needle protruded 9 mm past the Tuohy tip, compared with a 0% failure when a 127 mm Gertie Marx needle protruded 17 mm past the Tuohy needle tip.²⁷  Thus failure to obtain an adequate spinal blockade can be attributed to a non-midline approach, excessive movement of the spinal needle within the epidural needle, and inadequate spinal needle protrusion the past the epidural needle tip (minimum 12-13 mm).

Longer spinal needles increase the likelihood of anterior dural puncture and CSF leak.  Riley et al.²⁷  reported a higher incidence of post-dural puncture headache and blood patch requirement in the 127 mm Gertie Marx group than the 120 mm Sprotte group but this difference was not statistically significant. Longer spinal needles may also cause transient paresthesias.  Herbstman noted a 29% incidence of paresthesias with Gertie Marx needles compared to a 17% incidence with the shorter Whitacre needle.²⁸ Van Den Berg found that the type of 27g needle used during CSE influcenced paresthesia rate. 27g pencil-point needles were found to have a significantly higher rate of paresthesias, grimacing, and movement than 27g cutting edge needles.²⁹

Pharmacological Choices for CSE: Opioids and Local Anesthetics

Sufentanil and Fentanyl are the most commonly used intrathecal opioids administered for labor anesthesia to supplement low-dose local anesthetic (e.g., isobaric bupivacaine, ropivicaine or levobupivacaine) to provide a dense sensory block while preserving motor function.  Standard intrathecal Sufentanil doses are 2.5-10 mcg with an ED50 of 2.6 mcg (Table 4).⁴  Standard intrathecal Fentanyl doses are 10-25 mcg with an ED50 of 5.5 mcg.⁴  These opioids cause rapid (within 5 minutes) and dense pain relief during stage 1 and 2 of labor.³⁴  Intrathecal Morphine and Meperidine have delayed onset time and a higher incidence of delayed respiratory depression, pruritus, nausea, and vomiting.^4,34

 

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Table 4. Standard Intrathecal Opioid Doses for Labor Analgesia⁴

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From: “Combined Spinal-Epidural (CSE) Anesthesia." The New York School of Regional Anesthesia. 2009-03-08. 00:51:00. http://www.nysora.com/regional_anesthesia/neuraxial_techniques/3046-Combined-SpinalEpidural-CSE-Anesthesia.html

 

 

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Commonly used local anesthetics in CSE anesthesia are bupivicaine, ropivacaine and levobupivacaine, with bupivacaine producing the most intense motor blockade (Tables 5 and 6).³⁵  Intrathecal bupivacaine reduces intrathecal fentanyl requirements by up to 20 mcg.⁴  Limiting the intrathecal opioid dose can decrease the risk of pruritus, fetal bradycardia, and maternal respiratory depression (common opioid related side effects).³⁴ 

 

 

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Table 5. Median Effective Local Anesthetic Intrathecal Doses for Motor Blockade in Parturients (Bromage Scale 1-3 Feet/Knees)

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From: Camorcia M., Capogna G., Berritta C. and Columb M.  The relative potencies for motor block after intrathecal ropivacaine, levobupivacaine, & bupivacaine.  Anesth Analg 2007;104:904-907

 

 

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Table 6. Relative Motor Blocking Potency Ratios

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From: Camorcia M., Capogna G., Berritta C. and Columb M.  The relative potencies for motor block after intrathecal ropivacaine, levobupivacaine, & bupivacaine.  Anesth Analg 2007;104:904-907

 

 

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Obstetric Anesthesia 

 

CSE anesthesia is widely used in obstetric anesthesia.  Initiating neuraxial analgesia with a low-dose intrathecal opioid and local anesthetic followed by an epidural maintenance infusion has been found to preserve motor function while providing rapid onset of pain relief in laboring women.5  CSE allows for ambulation and preservation of pelvic musculature to facilitate delivery and provides adequate sacral analgesia when compared to epidural alone.^6,34,36 

Rapid relief of severe labor pain has been implicated in the development of uterine tetany and subsequent fetal bradycardia.  A sudden decrease in circulating maternal cathecholmines may lead to an imbalance between epinephrine and norepinephrine resulting in unapposed alpha-adrenoreceptor effects on uterine tone and decreased uteroplacental perfusion.  However, changes in uterine tone following neuraxial analgesia have not been shown to increase operative delivery rate or adverse neonatal outcome.^37,38

Whether CSE anesthesia results in a higher incidence of non-reassuring fetal heart rates and fetal bradycardia when compared to epidural anesthesia alone is currently a topic of debate.^{4,5,34,37,38,39}  Studies have reported an increased frequency of non-reassuring fetal heart rate patterns (3.9-12% incidence), particularly fetal bradycardia, when high doses of intrathecal opiods were used (50 mcg of fentanyl and 7.5-10 mcg of sufentanil).³⁹  Wong et al. described an increase in late fetal heart rate decelerations in association with CSE anesthesia (fentanyl 2 mcg/ml + bupivacaine 0.625 mg/ml infused at 15 mL per hour + 5 mL allowable bolus; maximum 30 mL per hour).⁵   However, when compared to systemic analgesia, neonatal outcomes (e.g., one-minute Apgar scores) were more favorable in the CSE group.⁵  Furthermore, when comparing CSE to epidural technique, no difference was seen in the overall rate of prolonged fetal heart  rate deceleration.³⁹ 

The 2009 Cochrane review on CSE versus epidural for labor analgesia comprises 2658 women enrolled in nineteen trials.  Of the twenty-six outcomes observed, only four were found to be statistically significant.  CSE had a faster onset of effective analgesia, lower need for rescue analgesia, a lower incidence of urinary retention, and a higher incidence of pruritus.  There was no difference in maternal satisfaction, mobilisation during labor, post-dural puncture headaches, caesarean section rates, umbilical cord pH, Apgar scores at five minutes or the number of neonates requiring NICU admission.

Adverse Effects

Intrathecal Catheter Migration 

Intrathecal catheter migration is a rare occurrence that usually occurs after dural puncture with a large gauge Tuohy needle.  Holmstrom et al. demonstrated intrathecal catheter migration in 9/20 cadaver models after dural puncture with a large gauge (16-18) Tuohy needle.⁴¹  In cases where a 25-gauge spinal needle was used, catheter migration was noted in only 1/20 cases, and only in models that received five spinal needle punctures.  In the models with only one 25 gauge spinal needle dural puncture, catheter migration did not occur.⁴¹  In another study, catheter migration did not occur despite the use of endoscopic control to direct the epidural catheter through a 27 gauge Quincke needle puncture site.⁴²  Therefore, epidural catheter migration appears to be a function of the size of needle used, and the number of dural punctures.  Some clinicians advocate rotating the epidural needle 180 degrees prior to catheter insertion in order to redirect the catheter away from the dural puncture site.  This, however, is not without risk, as it may increase the likelihood of dural puncture.⁴³ 

Infectious Complications 

Meningitis and epidural abscess are rare complications of neuraxial blockade. ^9,39  English publications reviewed on Pubmed between 1978-2007 revealed 107 documented cases of meningitis attributed to neuraxial anesthesia⁴⁴  The most common etiologic agent implicated was Streptococcal species (43%), followed by Gram negatives (10.3%), and staphylococci (8.4%).  In 41 cases, the causitive agent was not identified, most likely because of antibiotic administration prior to obtaining an adequate culture.

 

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Table 7. Agents Implicated in Iatrogenic Meningitis⁴⁴

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Streptocococcal  43% overall	Gram Negatives 10.3% overall	Staphylococci 8.4% overall
Alpha-hemolytic/Viridans group streptococci 38%	Pseudomonas aeruginosa 7.5%	Staphylococcus Aureus 5.6%
Streptococcus salivarius 16.8%	Escherichia coli 1.9%	Coagulase-negative Staphylococcus 2.8%
Streptococcus mitis  4.7%	Neisseria meningitidis 0.9%
Streptococcus sanguis  2.8%
Enterococcus spp   2.8%
Streptococcus pneumoniae 1.7%
Group D streptococci  1.7%
Streptococci Cremoris  0.9%
Streptococci Uberis  0.9%
Unspeciated Streptococci  9%

 

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The most likely sources are from droplet contamination from staff performing the dural puncture, and needle contamination due to incompletely sterilized skin.  Alpha-hemolytic streptococci from the nasopharynx of one anesthesiologist were responsible for four cases of meningitis over a 4-year period.  The strains were molecularly matched and traced to the same anesthesiologist who had a history of frequent pharyngitis and did not wear a mask.  Staphylococcus is the most common agent implicated in the development of epidural abscesses and usually presents in immunocompromised patients.⁴⁴  Additional attention to aseptic technique should be taken with CSE placement because dural puncture is followed by nearby placement of an indwelling catheter that can serve as a nidus for infection thereby theoretically compounding the risk of an infection. 

 

Metal Toxicity 

Care must be taken to avoid passage of foreign material into the neuraxial space.  Critics initially expressed concern that the NTN technique increased the risk of ultrafine metal shavings, created from friction between the spinal needle and the epidural needle, being introduced into the intrathecal or epidural space.  However, an in-vitro study using atomic absorption spectrography and electron microscopy showed no detectable metal contamination occurred despite using an intentionally rough NTN technique.   Furthermore, there have been no documented cases of neurologic complications arising from metal toxicity.

Summary 

• Catheters placed with a CSE technique versus an epidural have a lower rate of failure.
• Local anesthetic flux from the epidural space to the intrathecal space has been reported to improve the quality of neuraxial blockade when CSE is performed with a 26 gauge needle, but not 27 or 29 gauge needles. 
• Thecal sac compression occurs after bolus administration in the epidural space and can result in cephalad displacement of spinal anesthetic.  This phenomenon is known as epidural volume extension.
• Epidurals are associated with a higher incidence of cardiac arrest and mortality when compared to single shot spinals and CSEs.
• The separate-needle CSE technique has a decreased conversion rate to general anesthesia when compared to the needle-through-needle CSE technique.
• Failure of the spinal component of the CSE is usually attributable to movement of the spinal needle out of the thecal sac during injection, a lack of spinal needle protrusion beyond the epidural needle tip, or off-midline advancement of the epidural needle.
• Both CSEs and epidurals are associated with fetal bradycardia.  Neuraxial analgesia-induced fetal bradycardia has not resulted in increased rates of caesarean delivery, or worsened fetal or maternal outcomes.
• Meningitis and epidural abscesses are rare complications from neuraxial interventions, with Streptococci, Gram negative organisms, and Staphylococci being the predominant causative microorganisms.

References 

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2. Curelaru, I. Long Duration Subarachnoid Anesthesia with Continuous Epidural Block. Prakt Anasth 1979;14:71-78
3. Brown D.  Spinal, Epidural & Caudal Anesthesia.  Editors: Miller R., Fleisher L., Johns R.,Savarese J., Wiener J., and Young W. Anesthesia (6th ed.), New York:Churchill Livingstone, 2005, 1653-1679.
4. “Combined Spinal-Epidural (CSE) Anesthesia." The New York School of Regional Anesthesia. 2009-03-08. 00:51:00. http://www.nysora.com/regional_anesthesia/neuraxial_techniques/3046-Combined-SpinalEpidural-CSE-Anesthesia.html
5. Wong C, Scavone B, Peaceman A, et al. The risk of cesarean delivery with neuraxial analgesia given early versus late in labor. N Engl J Med 2005;352:655-665
6. Suzuki N, Koganemaru M, Onizuka S, et al. Dural puncture with a 26G spinal needle affects spread of epidural anesthesia. Anesth Analg 1996;82:1040-4
7. Holst D, Mollman M, Schymroszcyk B, et al. No Risk of Metal Toxicity in Combined Spinal-Epidural Anesthesia. Anesth Analg 1999;88:393-397
8. Norris, MC.  Are Combined Spinal-Epidural Catheters Reliable?  Intl J Obstet Anesth 2000;9:3-6
9. Miro M., Guasch E., Gilsant F.  Comparison of epidural analgesia with combined spinal epidural analgesia for labor: a retrospective study of 6,497 cases.  Intl J Obstet Anesth 2008;17:15-19
10. Higuchi H, Adachi Y, Kazama T.  Effects of epidural saline injection on cerebrospinal fluid volume and velocity waveform: a magnetic resonance imaging study.  Anesthesiology 2005;102:285-92
11. Stienstra R, Ban Z, and Dilrosun-Alhadi.  The Epidural “top-up” in combined spinal-epidural anesthesia: The effect of volume versus dose.  Anesth Analg 1999;88:810-814
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18. Casati A, D’Ambrosio A, De Negri P, et al.  A clinical comparison between needle-through-needle and double-segment techniques for combined spinal and epidural anesthesia.  Reg Anesth Pain Med 1998; 23:390-394
19. Sadashivaiah S, Wilson R, McLure H, et al. Double-spaced combined spinal-epidural technique for elective caesarean section: a review of 10 years’ experience in a UK teaching maternity unit.  Intl J Obstet Anesth 2010;19:183-187
20. Garry M., Davies S. Failure of regional blockade for caesarean section.  Intl J Obstet Anesth 2002;11:9-12
21. Pan PH., Bogard TD., Owen MD.  Incidence and characteristics of failures in obstetric neuraxial analgesia and anesthesia: a retrospective analysis of 19259 deliveries.  Intl J Obstet Anesth 2004;13:227-33
22. Kinsella SM.  A prospective audit of regional anaesthesia failure in 5080 Caesarean sections.  Anaesthesia 2008;63:822-32
23. Viira DJ., Courtman S., Coghill J.  Technical difficulties and complication rates of combined spinal epidural anaesthesia for elective and non-elective caesarean section.  Intl J Obstet Anesth2008;17:86-87
24. Grau T, Leipold W, and Martin E.  Real-time ultrasonic observation of combined spinal-epidural anaesthesia.  Eur J Anaesth 2004;21:25-31
25. Stocks G, Hallworth S, and Fernando R.  Evaluation of a spinal needle locking device for use with the combined spinal epidural technique.  Anaesthesia 2000;55:1185-1188
26. Norris, M., Grieco W., Borkowski M. Complications of Labor Analgesia: Epidural Versus Combined Spinal Epidural Techniques.  Anesth Analg 1994;79:529-537
27. Joshi G and McCarrol S.  Evaluation of combined spinal-epidural anaesthesia using two different techniques.  Reg Anaesth 1994;55:169-174
28. Riley E, Hamilton C, Ratner E, et al. A comparison of the 24-gauge sprotte and gertie marx spinal needles for combined spinal-epidural analgesia during labor.  Anesthesiology 2002;97:574-577 
29. Herbstman C, Jaffe J, Tuman K, et al.  An in vivo evaluation of four spinal needles used for the combined spinal-epidural technique.  Anesth  Analg 1998;86:520-522
30. Grau T, Leiopold RW., Horter J, et al.  Paramedian access to the epidural space: the optimum window for ultrasound imaging.  J Clin Anesth  2001;13:213-217.
31. Karmaker M., Li X., Ho A., et al.  Real time ultrasound-guided paramedian epidural access: evaluation of a novel in-plane technique.  Br J Anaesth 2009;102:845-854
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